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Effect of Liver Fat on Insulin Extraction and Pancreatic Beta-cell Function

Non-alcoholic fatty liver disease may impair pancreatic beta-cell function…. 

In this cross-sectional analysis, researchers assessed how liver fat influences hepatic insulin extraction and indices of pancreatic beta cell function.

Study participants included 70 healthy volunteers from the Hertfordshire Physical Activity Trial, which including 39 adult males (mean age 71.3 years). Study participants were given an oral glucose tolerance test; with resulting glucose, insulin and c-peptide levels measured every 30 minutes, for a duration of 2 hours. Researchers then used the AUC for these corresponding data points to quantitatively assess the following variables: hepatic insulin extraction, the insulinogenic index, the c-peptide increment, the disposition index and adaptation index. Further, researchers quantified visceral fat, using MRI, as well as intrahepatic lipids.

In both groups of study participants, alcohol consumption, age, HbA1c and alanine aminotransferase levels were identical. 41% of study participants exceeded the defined threshold for non-alcoholic fatty liver disease (defined as intrahepatic lipid >5.5%). Study participants with non-alcoholic fatty liver disease were found to have higher body weight, BMI, waist circumference and larger amounts of visceral fat compared to individuals with normal liver fat.

Individuals with non-alcoholic fatty liver disease had lower insulin sensitivity and lower hepatic insulin extraction ratio. A small but statistically significant inverse association was observed between intrahepatic lipids and hepatic insulin extraction when those with abnormal intrahepatic lipids were compared to individuals with normal intrahepatic lipids (hepatic insulin extraction 88.1 verse 85.6%, respectively: adjusted beta = -0.2,-0.3 to -0.06, P < 0.006). This corresponds to a 1% increase in intrahepatic lipids for every 0.2% reduction in hepatic insulin extraction. A positive association between insulin secretion and intrahepatic lipids was noted however no significant associations between intrahepatic lipids and the insulin-derived indices of beta-cell function (insulinogenic index and disposition index) were found. In contrast, an inverse association between intrahepatic lipids and c-peptide derived measures of beta-cell function (c-peptide-genic index and adaptation index) was found, showing that increased levels of hepatic fat accumulation were associated with a decrease in c-peptide secretion from pancreatic beta-cells. Upon adjusting for insulin sensitivity measured using oral glucose insulin sensitivity, the strength of this association became somewhat diminished (beta = -11.5, -23.7 to 0.59, P = 0.062). Insulin and c-peptide secretion after oral glucose were higher in participants with increased intrahepatic lipids. However, when insulin and c-peptide secretion following oral glucose administration was quantified in the context of dynamic glucose excursions increased intrahepatic lipids were ultimately found to be associated with a reduction in beta-cell function according to c-peptide based model parameters. This was apparent only once c-peptide was measured and taken into context with insulin sensitivity and glucose level changes.

Practice Pearls:
  • Associations between non-alcoholic fatty liver disease and type 2 diabetes are well-known, however the mechanism behind this association is not completely understood
  • In non-alcoholic fatty liver disease, beta-cell dysfunction may be a factor in elevated insulin levels and may be obscured by reduced hepatic insulin extraction due to liver fat
  • Additional studies which quantify the content of pancreatic fat as well as the influence on beta-cell function are needed for understanding the mechanism of this

Finucane FM, Sharp SJ, Hatunic M, Sleigh A, De Lucia Rolfe E, Sayer AA, Cooper C, Griffin SJ, Wareham NJ. Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals Diabetology & Metabolic Syndrome 2014, 6:43 (26 March 2014) http://www.dmsjournal.com/content/6/1/43